1. Field of Invention
The present invention relates to some novel 2-aryl and 2,2-diaryl aldehydes and analogues which are privileged intermediates for commercially important nonsteroidal anti-inflammatory drugs including naproxen, flurbiprofen and potent anticancer drug candidates including hydroxy phenstatin are synthesized through a novel microwave induced process which not only provides the highly valuable 2-aryl and 2,2-diaryl aldehydes from the corresponding aryl alkenes in a single step but also simultaneously eliminates the hitherto indispensable requirement of expensive and hazardous transition metal catalysts.
2. Background Art
The 2-aryl aldehyde constitutes an immensely important synthon for the synthesis of various commercially and pharmacologically valuable compounds. For instance, the commercially important non steroidal anti-inflammatory drugs like naproxen (2-(6′ methoxy-2′-naphthyl)-propionic acid) and ibupfren (2-(4′-isobutylphenyl)-propionic acid) are alpha aryl alkanoic acids and their analogues which are synthesized through various synthetic approaches including the oxidation of corresponding 2-aryl aldehydes (C. Commun. 2007, 1739-1741; J. Org. Chem. 1999, 64, 5029-5035, Organometallics 10, 1183-1189, 1991, 1183, WO 9303839). In particular, naproxen has been widely recognized as an ace anti-inflammatory agent and ranked fourth in sales in the global pharmaceutical market in 1991. Similarly ibupfren is a well known anti-inflammatory drug which has been converted from ethical (prescription) to the counter status. Besides their synthesis using 2-aryl aldehydes as intermediates, the above 2-aryl alkanoic acids have also been synthesized from various other approaches, principal amongst them being the carbonylation of respective arylethyl alcohols (Japanese Kokai patent No SHO 55 (1980)-27147), electrocarboxylation of corresponding aryl methyl ketones (U.S. Pat. No. 4,601,797, Japanese patent J60100536, J60103193 and EP-A-189120), or carbonylation of secondary benzyl halides (J. Organometallic chemistry 282, (1985) 277-282, U.S. Pat. No. 4,536,595, EP Nos. 76721, 76722, or by the coupling of alpha-halopropionic acid with 2-(6-methoxynaphthyl) copper (U.S. Pat. No. 3,658,863), zinc (U.S. Pat. No. 3,663,584), cadmium (U.S. Pat. Nos. 3,658,858 and 3,694,476) or coupling of aryl magnesium halides with potassium 2-iodopropionate (German OLS No. 2145650) or reaction of aryl Grignard reagent with lithium, sodium, magnesium salts of 2-bromopropionic acids (U.S. Pat. No. 3,959,364) or carbonylation of aryl halide with CO and cobalt catalyst (U.S. Pat. No. 3,974,202), Palladium catalyst (U.S. Pat. No. 4,713,484) or by the arrangement of alpha-haloketals in the presence of a lewis acid (EP No. 0034871).
However, all above methods suffer from one or the other limitations like multistep synthesis, use of expensive and hazardous organometallic agents besides the problems in maintenance of high CO pressure.
In view of the above concerns, there have been continuing efforts to develop alternative synthetic approaches towards the immensely important 2-aryl alkanoic acid framework. In this context, the synthesis of 2-aryl alkanoic acids through the respective 2-aryl aldehydes as a useful synthon constitutes a simple and straight forward procedure which has been described in the prior art (C. Commun. 2007, 1739-1741, /. Org. Chem. 1999, 64, 5029-5035, Organometallics 10, 1183-1189 1991, WO 9303839).
In addition to their above usefulness as critical intermediates for the synthesis of commercially important anti-inflammatory drugs, the various other 2-aryl aldehyde analogues and especially the 2,2-diaryl aldehydes have recently been found to be privileged structural motifs for accessing some new potent anticancer compounds (U.S. Pat. No. 6,943,194 B1, J. Org. Chem. 1996, 65, 7438-7444). In particular, the above prior art discloses the formation of some novel trimethoxystilbene based benzophenone derivatives namely hydroxy phenstatin which showed potent inhibition of tubulin assembly (IC50=0.82, U M) and exhibited an ED50 of 0.25 μg/ml against the P388 lymphocytic leukemia cell lines, thus establishing their potent antitumor and antimitotic credentials. In the light of above discussion, it would be clear that a putative stilbene based benzophenone scaffold holds immense potential for displaying useful medicinal properties including anticancer activities. However, the synthesis of above medicinally important compounds themselves depend on the availability of critical synthons including the corresponding 2,2-diaryl aldehydes as evident in the prior art (U.S. Pat. No. 6,943,194 B1, /. Org. Chem. 1996, 65, 7438-7444). It is also evident that the various 2-aryl aldehydes and analogues such as 2,2-diaryl aldehydes constitute a privileged class of compounds with diverse applications for the synthesis of commercially and medicinally important compounds. However, the development of a convenient and economical protocol for the synthesis of above synthon i.e. 2-aryl aldehydes from easily available substrates like aryl alkenes has in itself remained tedious and expensive proposition. For instance, Organometallics 1991, 10, 1183-1189 discloses a method for multistep synthesis of 2-aryl aldehydes from the corresponding aryl ethenes utilizing expensive and hazardous reagents like rhodium catalyst and BINAPHOS ligand.
Similarly, J. Org. Chem. 1997, 62, 6547-6561 discloses a method for the formation of 2-aryl and 2,2-diaryl aldehydes via a multistep methodology involving the formation of epoxide from aryl alkene and its subsequent rearrangement using toxic palladium catalyst and phosphine ligands.
Similarly, J. Org. Chem. 1998, 63, 8212-8216 discloses a multistep method for the formation of 2-aryl and 2,2-diaryl aldehydes from respective aryl alkenes via the rearrangement of an intermediate epoxide using rare and expensive InCl3 as a lewis acid.
In yet another instance, 2-aryl aldehydes were synthesized via the rearrangement of epoxides obtained from the corresponding aryl alkenes using lithium perchlorate as a lewis acid catalyst (J. Org. Chem. 1996, 61, 1877-1879).
Similarly, the 2-aryl and 2,2-diaryl aldehydes were synthesized via the rearrangement of corresponding epoxides using expensive IrCl3 as a lewis acid catalyst (Tetrahedron Lett. 44, 2003, 7687-7689).
In a Similar manner, J. Org. Chem. 1996, 65, 7438-7444 discloses the multistep formation of 2,2-diaryl aldehydes from the corresponding stilbenes using boron trifluoride etherate catalyst.
In another instance, 2-aryl aldehydes were synthesized from the corresponding aryl alkenes, however, the methodology required an indispensable usage of base catalyst in the form of hazardous heavy metal salts like silver oxide etc. which precludes its use in case of substrates containing base sensitive groups. (Chem. /ett. 1984, 341-344). In addition, the above methodology might also lead to production of corresponding carboxylic acids, as undesired side product, due to the known tendency of silver oxides for such a transformation (Tetrahedron: Asymmetry, 2005, 16, 1837-1843).
In view of the above, it is quite apparent that there has been a dearth of convenient protocols for the direct synthesis of 2-aryl aldehydes and analogues such as 2,2-diaryl aldehydes from corresponding arylalkenes as almost all the prevalent methods utilize multiple steps involving an intermediate epoxide besides the use of toxic, rare, and expensive transition metal/organometallic catalysts.
Thus, it becomes an object of the present invention to develop a convenient, economical and environment friendly synthetic methodology which not only provides the highly valuable 2-aryl and 2,2-diaryl aldehydes from the corresponding aryl alkenes in a single step but also simultaneously eliminates the hitherto indespensible requirement of expensive and hazardous transition metal catalysts.